Pharmaceutical composition containing celecoxib

ABSTRACT

Disclosed herein is a pharmaceutical composition comprising pharmaceutical formulation of complexed Celecoxib and crystalline Celecoxib to provide fast and long lasting continuous pain management with once a daily dosing. The pharmaceutical composition has improved physicochemical properties that provide faster onset of action for acute pain relief and lower GI related side effects for acute pain relief and lower GI related side effects.

This application is a continuation of U.S. patent application Ser. No.16/136,920, filed Sep. 20, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/840,204, filed Dec. 13, 2017, now issued U.S.Pat. No. 10,080,762, which claims priority to U.S. provisionalapplication No. 62/434,173, filed Dec. 14, 2016, and U.S. provisionalapplication No. 62/502,170, filed May 5, 2017, the disclosures of whichare hereby incorporated by reference as if written herein in theirentireties.

FIELD OF THE INVENTION

Disclosed herein are pharmaceutical compositions comprising a mixture ofa pharmaceutical formulation of complexed Celecoxib and crystalline,uncomplexed Celecoxib to provide fast and long lasting continuous painmanagement with once daily dosing. The pharmaceutical compositions areuseful in the treatment of osteoarthritis, rheumatoid arthritis,juvenile rheumatoid arthritis, ankylosing spondylitis, acute pain,primary dysmenorrhea. Further disclosed are methods of manufacturing thepharmaceutical compositions.

BACKGROUND OF THE INVENTION

The chemical name of Celecoxib is4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and is a diaryl-substituted pyrazole. The molecularformula is C₁₇H₁₄F₃N₃O₂S, and the molecular weight is 381.38; thechemical structure is as follows:

Celecoxib is a white powder, insoluble in water, soluble in methanol andchloroform.

CELEBREX oral capsules contain either 50 mg, 100 mg, 200 mg or 400 mg ofCelecoxib, together with inactive ingredients including: croscarmellosesodium, edible inks, gelatin, lactose monohydrate, magnesium stearate,povidone and sodium lauryl sulfate.

CELEBREX is a nonsteroidal anti-inflammatory drug that exhibitsanti-inflammatory, analgesic, and antipyretic activities in animalmodels. The mechanism of action of CELEBREX is believed to be due toinhibition of prostaglandin synthesis, primarily via inhibition ofcyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans,CELEBREX does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme. Inanimal colon tumor models, CELEBREX reduced the incidence andmultiplicity of tumors.

Peak plasma levels of Celecoxib occur approximately 3 hrs after an oraldose. Under fasting conditions, both peak plasma levels (C_(max)) andarea under the curve (AUC) are roughly dose-proportional up to 200 mgBID; at higher doses there are less than proportional increases inC_(max) and AUC. Absolute bioavailability studies have not beenconducted. With multiple dosing, steady-state conditions are reached onor before Day 5.

When CELEBREX capsules were taken with a high fat meal, peak plasmalevels were delayed for about 1 to 2 hours with an increase in totalabsorption (AUC) of 10% to 20%. Under fasting conditions, at doses above200 mg, there is less than a proportional increase in C_(max) and AUC,which is thought to be due to the low solubility of the drug in aqueousmedia.

Co-administration of CELEBREX with an aluminum- and magnesium-containingantacids resulted in a reduction in plasma celecoxib concentrations witha decrease of 37% in C_(max) and 10% in AUC. CELEBREX, at doses up to200 mg twice daily, can be administered without regard to timing ofmeals. Higher doses (400 mg twice daily) should be administered withfood to improve absorption.

In healthy adult volunteers, the overall systemic exposure (AUC) ofCelecoxib was equivalent when Celecoxib was administered as intactcapsule or capsule contents sprinkled on applesauce. There were nosignificant alterations in C_(max), t_(max) or t_(1/2) afteradministration of capsule contents on applesauce.

In healthy subjects, Celecoxib is highly protein bound (˜97%) within theclinical dose range. In-vitro, studies indicate that Celecoxib bindsprimarily to albumin and, to a lesser extent, α1-acid glycoprotein. Theapparent volume of distribution at steady state (Vss/F) is approximately400 L, suggesting extensive distribution into the tissues. Celecoxib isnot preferentially bound to red blood cells.

Celecoxib metabolism is primarily mediated via CYP2C9. Threemetabolites, a primary alcohol, the corresponding carboxylic acid andits glucuronide conjugate, have been identified in human plasma. Thesemetabolites are inactive as COX-1 or COX-2 inhibitors.

Celecoxib is eliminated predominantly by hepatic metabolism with little(<3%) unchanged drug recovered in the urine and feces. Following asingle oral dose of radiolabeled drug, approximately 57% of the dose wasexcreted in the feces and 27% was excreted into the urine. The primarymetabolite in both urine and feces was the carboxylic acid metabolite(73% of dose) with low amounts of the glucuronide also appearing in theurine. It appears that the low solubility of the drug prolongs theabsorption process making terminal half-life (t½) determinations morevariable. The effective half-life is approximately 11 hours under fastedconditions. The apparent plasma clearance (CL/F) is about 500 mL/min.

The main medical concerns surrounding Celecoxib are related to slowabsorption and variable first-pass metabolism of Celecoxib limit itsutility for treatment of acute pain. When a single dose of 200 mg ofcurrent formulation is given, peak plasma levels occur 3 hours after anoral dose, however, onset of pain relief could be as early as 1 hour.When taken with a high fat meal, peak plasma levels are delayed forabout 1 to 2 hours with an increase in total absorption (AUC) of 10% to20%. Since it is a painkiller shortening this time and the eliminationof the delay of peak plasma concentrations could be advantageous.

In order to overcome the problems associated with prior conventionalCelecoxib formulations and available drug delivery systems, novelpharmaceutical compositions of Celecoxib comprising the pharmaceuticalformulation of complexed Celecoxib and crystalline Celecoxib wereprepared. The pharmaceutical formulation ensures the immediateabsorption of Celecoxib via the complexed formulation, resulting in fastpain relief, while the crystalline component is responsible for delayedabsorption and extended analgesic effect.

A variety of strategies have been used to attempt to overcome theseissues, see for example US 20130338131, WO 2009114695, U.S. Pat. No.7,879,360, US 20090098200, WO 2003080027, US 20150011514, U.S. Pat. Nos.6,964,978, 7,220,867, WO 2001042221, WO 2001095877, WO 2001091750, WO2014018932, WO 2004078163, WO 2004047752, WO 2007010559, WO 2013132457and WO 2001041760.

DESCRIPTION OF THE INVENTION

Disclosed herein are pharmaceutical compositions comprising the mixtureof a complexed pharmaceutical formulation of Celecoxib and crystallineCelecoxib; said pharmaceutical compositions are characterized in thatthey possess at least one of the following properties:

-   -   a) is instantaneously redispersable in physiological relevant        media;    -   b) has an apparent solubility in water of at least 1 mg/mL;    -   c) has biphasic dissolution profile: complexed pharmaceutical        formulation of Celecoxib dissolves from the composition within        45 minutes, while crystalline Celecoxib has continuous        dissolution;    -   d) has a PAMPA permeability of at least 0.5×10⁻⁶ cm/s when        dispersed in fasted state simulated intestinal fluid (FaSSIF) or        fasted state simulated intestinal fluid (FeSSIF) biorelevant        media; which does not decrease in time at least for 3 months        stored at 40° C.    -   e) has a blood plasma level that reaches 250 ng/ml Celecoxib in        less than 60 minutes when administered orally.

In an embodiment, said composition further comprises a pharmaceuticallyacceptable excipient.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within 30 minutes.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within 15 minutes.

In an embodiment, said blood plasma level is reached in less than 45minutes.

In an embodiment, said blood plasma level is reached in less than 30minutes.

In an embodiment, said blood plasma level is reached in less than 20minutes.

In an embodiment, said blood plasma level is reached in less than 15minutes.

In an embodiment, said plasma concentration is maintained for at least12 hours.

The complexed pharmaceutical formulation comprising complexed Celecoxibensures the immediate absorption of Celecoxib resulting in fast painrelief, while the crystalline component is responsible for delayedabsorption and extended analgesic effect.

It has been found that only the combination of pharmaceuticalformulation of complexed Celecoxib and crystalline Celecoxib resulted ina pharmaceutical composition which delivers early therapeutic bloodplasma levels which is at least 250 ng/mL to ensure the fast pain reliefand sustained Celecoxib dissolution to maintain the therapeutic bloodplasma level for at least 12 h after the oral administration of thepharmaceutical composition.

In an embodiment said pharmaceutical formulation of complexed Celecoxibcomprises Celecoxib, a copolymer of vinylpirrolidone and vinyl acetate,and sodium lauryl sulfate.

In an embodiment, said pharmaceutical formulation of complexed Celecoxibcomprises

a. 5-40% by weight of Celecoxib, its salt, or derivatives thereof;

b. 40-80% by weight of a copolymer of vinylpyrrolidone and vinylacetate; and

c. 1-30% by weight of sodium lauryl sulfate

wherein the particle size of said pharmaceutical formulation is lessthan 200 nm.

In an embodiment, said copolymer of vinylpyrrolidone and vinyl acetateis copovidone.

In an embodiment, vinylpyrrolidone and vinyl acetate ratio in saidcopolymer is VP:VA=60:40.

In an embodiment said crystalline Celecoxib is a micronized Celecoxib.

In an embodiment said micronized Celecoxib has a particle size in therange of 5-50 μm.

In an embodiment, said pharmaceutical formulation of complexed Celecoxibhas an apparent solubility in water of at least 1 mg/mL.

In an embodiment, said pharmaceutical composition comprising a mixtureof pharmaceutical formulation of complexed Celecoxib and crystalline,uncomplexed Celecoxib has biphasic dissolution profile: pharmaceuticalformulation of complexed Celecoxib dissolves from the composition withinless than 45 minutes, while crystalline Celecoxib dissolves continuouslyfrom the pharmaceutical composition.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within less than 30 minutes.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within less than 15 minutes.

In an embodiment, Celecoxib blood plasma level reaches 250 ng/mLtherapeutic value in less than 60 minutes after the administration ofsaid pharmaceutical composition comprising a mixture of pharmaceuticalformulation of complexed Celecoxib and crystalline, uncomplexedCelecoxib.

In an embodiment, said blood plasma level is reached in less than 45minutes.

In an embodiment, said blood plasma level is reached in less than 30minutes.

In an embodiment, said blood plasma level is reached in less than 20minutes.

In an embodiment, said blood plasma level is reached in less than 15minutes.

In an embodiment, said pharmaceutical compositions comprising a mixtureof pharmaceutical formulation of complexed Celecoxib and crystalline,uncomplexed Celecoxib provide faster onset of action for acute painrelief and lower GI related side effects compared to the currentlyavailable formulations.

In an embodiment, said complexes possess at least two of the propertiesdescribed in a)-e).

In an embodiment, said complexes possess at least three of theproperties described in a)-e).

In an embodiment, said pharmaceutical compositions comprise 50-200 mgCelecoxib that is complexed and 50-400 mg crystalline Celecoxib.

In an embodiment, said pharmaceutical compositions comprise 75-125 mgCelecoxib that is complexed Celecoxib and 75-125 mg crystallineCelecoxib.

In an embodiment, said pharmaceutical formulation of complexed Celecoxibis prepared by mixing 2-propanolic solution containing Celecoxib andcopolymer of vinylpyrrolidone and vinyl acetate with an aqueous solutioncontaining sodium lauryl sulfate.

In an embodiment, a pharmaceutical composition comprises saidpharmaceutical formulation comprising a mixture of pharmaceuticalformulation of complexed Celecoxib and crystalline Celecoxib togetherwith a pharmaceutically acceptable carrier.

In an embodiment, said compositions further comprise additionalpharmaceutical excipients.

In an embodiment, said pharmaceutical composition is suitable for oral,pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal,intraperitoneal, ocular, otic, local, buccal, nasal, or topicaladministration.

In an embodiment, said compositions are suitable for oraladministration.

In an embodiment, said pharmaceutical compositions are for use in themanufacture of a medicament for the treatment of osteoarthritis,rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosingspondylitis, acute pain, primary dysmenorrhea.

In an embodiment, said pharmaceutical compositions are used for thetreatment of osteoarthritis, rheumatoid arthritis, juvenile rheumatoidarthritis, ankylosing spondylitis, acute pain, primary dysmenorrhea.

In an embodiment, a method of treatment of osteoarthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acutepain, primary dysmenorrhea comprises administration of a therapeuticallyeffective amount of the pharmaceutical composition as described herein.

In an embodiment, a method for reducing the therapeutically effectivedosage of Celecoxib compared to commercially available Celebrex®comprises oral administration of a pharmaceutical composition asdescribed herein.

In an embodiment, the therapeutically effective Celecoxib blood plasmalevel (250 ng/mL) is reached within less than 60 minutes after the oraladministration of said pharmaceutical formulation as described herein.

In an embodiment, said blood plasma level is reached in less than 45minutes.

In an embodiment, said blood plasma level is reached in less than 30minutes.

In an embodiment, said blood plasma level is reached in less than 20minutes.

In an embodiment, said blood plasma level is reached in less than 15minutes.

In an embodiment, food uptake has no effect on the early absorption ofthe compound and the time it takes to reach effective Celecoxib bloodplasma level (250 ng/mL).

In an embodiment, said complexes show reduced fed/fasted effect comparedto Celebrex®.

In an embodiment, said complexes have an onset of action of 12 minutes,which is faster than the existing formulations of Celecoxib.

In an embodiment the pharmaceutical compositions as described hereindeliver early therapeutic blood plasma levels which is 250 ng/mL toensure the fast pain relief and sustained Celecoxib dissolution tomaintain the therapeutic blood plasma level for at least 12 h after theoral administration of the pharmaceutical composition.

In an embodiment, said pharmaceutical composition as described hereinhas biphasic dissolution profile: pharmaceutical formulation ofcomplexed Celecoxib dissolves from the composition within 60 minutes,while crystalline Celecoxib has continuous dissolution.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within less than 45 minutes.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within less than 30 minutes.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within less than 20 minutes.

In an embodiment, said complexed pharmaceutical formulation of Celecoxibdissolves from the composition within less than 15 minutes.

In an embodiment, the pharmaceutical formulation of complexed Celecoxibis instantaneously redispersable in physiological relevant media.

In an embodiment, the pharmaceutical formulation of complexed Celecoxibhas an apparent solubility in water of at least 1 mg/mL.

In an embodiment, the pharmaceutical formulation of complexed Celecoxibhas a PAMPA permeability of at least 0.5×10⁻⁶ cm/s when dispersed inFaSSIF or FeSSIF biorelevant media, which does not decrease in time atleast for 3 months stored at 40° C.

In some embodiments, the pharmaceutical compositions may additionallyinclude one or more pharmaceutically acceptable excipients, auxiliarymaterials, carriers, active agents or combinations thereof. In someembodiments, active agents may include agents useful for the treatmentof any type of cancer.

The pharmaceutical composition as described herein can be formulated:(a) for administration selected from the group consisting of oral,pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal,intraperitoneal, ocular, otic, local, buccal, nasal, and topicaladministration; (b) into a dosage form selected from the groupconsisting of liquid dispersions, gels, aerosols, ointments, creams,lyophilized formulations, tablets, capsules; (c) into a dosage formselected from the group consisting of controlled release formulations,fast melt formulations, delayed release formulations, extended releaseformulations, pulsatile release formulations, and mixed immediaterelease and controlled release formulations; or (d) any combination of(a), (b), and (c).

The compositions can be formulated by adding different types ofpharmaceutically acceptable excipients for oral administration in solid,liquid, local (powders, ointments or drops), or topical administration,and the like.

In an embodiment, the dosage form is a solid dosage form.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, pills, powders (sachet), orally disintegratingtablet, immediate release tablets and granules. In such solid dosageforms, the pharmaceutical composition of Celecoxib is admixed with atleast one of the following: one or more inert excipients (or carriers):(a) fillers or extenders, such as, lactose, sucrose, glucose, mannitol,sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt,lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starches,microcrystalline cellulose, dicalcium phosphate, calcium carbonate,magnesium carbonate, magnesium oxide; (b) sweetening, flavoring, andperfuming agents such as saccharin, saccharin sodium, acesulfamepotassium, alitame, aspartame, glycine, inulin, neohesperidindihydrochalcone, neotame, sodium cyclamate, sucralose, tagatose,thaumatin, citric acid, adipic acid, fumaric acid, leucine, malic acid,menthol, propionic acid, tartaric acid; (c) binders, such as cellulosederivatives, acrylic acid derivatives, alginates, gelatin,polyvinylpyrrolidone, starch derivatives, dextrose, dextrates, dextrin,maltose, maltodextrin; (d) disintegrating agents, such as crospovidon,effervescent compositions, croscarmellose sodium and other cellulosederivatives, sodium starch glycolate and other starch derivatives,alginic acid, certain complex silicates and sodium carbonate; (e)solution retarders, such as acrylates, cellulose derivatives, paraffin;(f) absorption accelerators, such as quaternary ammonium compounds; (g)wetting agents, such as polysorbates, cetyl alcohol and glycerolmonostearate; (h) lubricants such as talc, stearic acid and itsderivatives, solid polyethylene glycols, sodium lauryl sulfate, glycerylbehenate, medium-chain triglycerides or mixtures thereof. For capsules,tablets, and pills, the dosage forms may also comprise buffering agents.

In an embodiment, the dosage form is a liquid dispersible granule,sachet, orally disintegrating tablet, chewing tablet, tablet forsolution, tablet for suspension and immediate release tablet.

In an embodiment, said complexed Celecoxib and crystalline Celecoxib,and optionally said excipients, are blended together, granulatedtogether, or combinations thereof.

In an embodiment, said dosage forms comprise the blended and/orgranulated pharmaceutical formulation of complexed Celecoxib andcrystalline Celecoxib together with pharmaceutically acceptableexcipients selected from the group of fillers or extenders, such as,lactose, sucrose, glucose, mannitol, sorbitol, dextrose, dextrates,dextrin, erythritol, fructose, isomalt, lactitol, maltitol, maltose,maltodextrin, trehalose, xylitol, starches, microcrystalline cellulose,dicalcium phosphate, calcium carbonate, magnesium carbonate, magnesiumoxide.

In an embodiment, said dosage forms comprise the blended and/orgranulated pharmaceutical formulation of Celecoxib and crystallineCelecoxib with pharmaceutically acceptable excipients selected from thegroup of sweetening, flavoring, and perfuming agents such as saccharin,saccharin sodium, acesulfame potassium, alitame, aspartame, glycine,inulin, neohesperidin dihydrochalcone, neotame, sodium cyclamate,sucralose, tagatose, thaumatin, citric acid, adipic acid, fumaric acid,leucine, malic acid, menthol, propionic acid, tartaric acid.

Further disclosed herein is a liquid dispersible granule, sachet, orallydisintegrating tablet, chewing tablet, tablet for solution, tablet forsuspension and immediate release tablet comprising

a. 5-95% pharmaceutical formulation of complexed Celecoxib;

b. 5-95% crystalline Celecoxib;

c. 5-95% fillers or extenders;

d. 0.5-25% binders;

e. 0.001-15% sweetening, flavoring, and perfuming agents;

f. 5-95% disintegrants

wherein said liquid dispersible granule, sachet, orally disintegratingtablet, chewing tablet, tablet for solution, tablet for suspension andimmediate release tablet disintegrates within 10 min in liquid.

In an embodiment, said disintegration time is between 0.1 min and 10min.

In an embodiment, said disintegration time is between 0.1 min and 5 min.

In an embodiment, said disintegration time is between 0.1 min and 3 min.

In an embodiment, said disintegration time is between 0.1 min and 1 min.

In an embodiment, said liquid dispersible granules of complexedCelecoxib formulation are obtained by wet or dry processes.

In an embodiment, the Hausner-ratio of the said liquid dispersiblegranules of complexed Celecoxib formulations is less than 1.25.

In an embodiment, the Hausner-ratio of the said liquid dispersiblegranules of complexed Celecoxib formulations is between 1.00 and 1.11.

In an embodiment, the particle size (D(90)) of said liquid dispersiblegranules of complexed Celecoxib formulations is less than 2000micrometers.

In an embodiment, 60-80% of the said liquid dispersible granules ofcomplex celecoxib formulations are in the size range of 160-800micrometers.

In an embodiment, said liquid is water, saliva, other physiologically orbiologically acceptable fluid or liquid.

In an embodiment, the dosage form is a liquid dispersible granule,sachet, orally disintegrating tablet, chewing tablet, tablet forsolution, tablet for suspension and immediate release tablet.

In an embodiment, said liquid dispersible granule, sachet, orallydisintegrating tablet, chewing tablet, tablet for solution, tablet forsuspension or immediate release tablet comprises the pharmaceuticalformulation of complexed Celecoxib and crystalline Celecoxib togetherwith pharmaceutically acceptable excipients selected from the group offillers or extenders, such as, lactose, sucrose, glucose, mannitol,sorbitol, dextrose, dextrates, dextrin, erythritol, fructose, isomalt,lactitol, maltitol, maltose, maltodextrin, trehalose, xylitol, starch.

In an embodiment, said liquid dispersible granule, sachet, orallydisintegrating tablet, chewing tablet, tablet for solution, tablet forsuspension or immediate release tablet comprises the pharmaceuticalformulation of complexed Celecoxib and crystalline Celecoxib togetherwith pharmaceutically acceptable excipients selected from the group ofsweetening, flavoring, and perfuming agents such as saccharin, saccharinsodium, acesulfame potassium, alitame, aspartame, glycine, inulin,neohesperidin dihydrochalcone, neotame, sodium cyclamate, sucralose,tagatose, thaumatin, citric acid, adipic acid, fumaric acid, leucine,malic acid, menthol, propionic acid, tartaric acid.

In an embodiment, said liquid dispersible granule, sachet, orallydisintegrating tablet, chewing tablet, tablet for solution, tablet forsuspension or immediate release tablet comprises the pharmaceuticalformulation of complexed Celecoxib and crystalline Celecoxib togetherwith pharmaceutically acceptable excipients selected from the group ofdisintegrants such as cross-linked polyvinylpyrrolidone, sodium-starchglycolate, croscarmellose-sodium, soy polysaccharides, colloidal silicondioxide.

Further disclosed herein is liquid dispersible granule, sachet, orallydisintegrating tablet, tablet, chewing tablet, tablet for solution,tablet for suspension and immediate release tablet comprising

-   -   a. 5-95% stable pharmaceutical formulation of complexed        Celecoxib;    -   b. 5-95% crystalline Celecoxib;    -   c. 0.5-95% fillers or extenders such as lactose, sucrose,        glucose, mannitol, sorbitol, dextrose, dextrates, dextrin,        erythritol, fructose, isomalt, lactitol, maltitol, maltose,        maltodextrin, trehalose, xylitol, starch;    -   d. 0.001-15% sweetening, flavoring, and perfuming agents such as        saccharin, saccharin sodium, acesulfame potassium, alitame,        aspartame, glycine, inulin, neohesperidin dihydrochalcone,        neotame, sodium cyclamate, sucralose, tagatose, thaumatin,        citric acid, adipic acid, fumaric acid, leucine, malic acid,        menthol, propionic acid, tartaric acid;    -   e. 0.5-25% wetting agents, such as docusate sodium, sodium        dodecyl sulfate, ammonium lauryl ether sulfate, benzalkonium        chloride, benzethonium chloride, cetyl trimethylammonium        bromide, polyoxyethelene alkylphenylethersm poloxamers,        polyoxyethelene fatty acid glycerides, sorbitan esters;    -   f. 5-95% disintegrants such as cross-linked        polyvinylpyrrolidone, sodium-starch glycolate,        croscarmellose-sodium, soy polysaccharides, colloidal silicon        dioxide;        wherein said liquid dispersible granule, sachet, orally        disintegrating tablet, chewing tablet, tablet for solution,        tablet for suspension and immediate release tablet disintegrates        within 10 min.

In an embodiment, said disintegration time is between 0.1 min and 15min.

In an embodiment, said disintegration time is between 0.1 min and 5 min.

In an embodiment, said disintegration time is between 0.1 min and 1 min.

In an embodiment, said liquid dispersible granules are obtained by wetor dry processes.

The pharmaceutical compositions of Celecoxib described herein showimprovements related to (1) physical and chemical stability, (2)instantaneous redispersibility, (3) stability in colloid solution ordispersion in the therapeutic time window, (4) increased apparentsolubility and permeability compared to the conventional Celecoxibformulation, (5) decreased time to onset of action for acute pain, (6)oral bioavailability, (7) decreased fed/fasted effect especially withrespect to onset of action, and (8) good processability compared toCelebrex®.

In an embodiment, said compositions have good/instantaneousredispersibility of solid pharmaceutical compositions of Celecoxib inwater and biologically relevant media, e.g.; physiological salinesolution, pH=1.6 HCl solution, FessiF and FassiF media and gastrointestinal fluids, and adequate stability in colloid solutions and/ordispersion in the therapeutic time window.

In an embodiment, said compositions have increased apparent solubilityand PAMPA permeability. In some embodiments, the apparent solubility andpermeability of said compositions is at least 1 mg/mL and 0.5×10⁻⁶ cm/s,respectively.

In another embodiment, the Celecoxib pharmaceutical compositions have anenhanced pharmacokinetic performance. The complex Celecoxib formulationsshow decreased time to onset of action when compared to the current oralformulation.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying figures, which are incorporated and form part of thespecification, merely illustrate certain embodiments and should not beconstrued as limiting the invention. They are meant to serve to explainspecific modes to those skilled in the art.

FIG. 1 shows the dissolution profile of Celecoxib pharmaceuticalcomposition, complexed Celecoxib pharmaceutical formulation andcrystalline Celecoxib (micronized).

FIG. 2 shows the cumulative dissolution of Celecoxib pharmaceuticalcomposition.

FIG. 3 shows the PAMPA permeability of different Celecoxib compositions:micronized Celecoxib, Celebrex, complexed Celecoxib formulations andCelecoxib pharmaceutical formulation.

FIG. 4 shows the PAMPA permeability of Celecoxib pharmaceuticalcomposition at t=0 and t=12 months when stored at 40° C. and complexedCelecoxib formulation stored at 40° C. at t=3 months

FIG. 5 shows the plasma concentrations of celecoxib following theadministration of the following test items orally as dispersedgranulates: complexed pharmaceutical formulation (2.5 mg/kg), micronizedCelecoxib (5 mg/kg), pharmaceutical composition as described herein (2.5mg pharmaceutical formulation and 5 mg/kg crystalline micronizedcelecoxib) to beagle dogs following a high-fat meal (N=4).

EXAMPLES

Specific, non-limiting embodiments will further be demonstrated by thefollowing examples.

Celecoxib Pharmaceutical Formulations

A solution mixture of complexed Celecoxib pharmaceutical formulation wasprepared by mixing process. 2-propanolic solution (Solution 1)containing 10 mg/mL Celecoxib 40 mg/mL copovidone (copolymer ofvinylpyrrolidone and vinyl acetate/Kollidon VA64) was mixed with aqueoussolution (Solution 2) containing 20 mg/mL sodium lauryl sulfate. Thesolution mixture was produced at atmospheric pressure and ambienttemperature. The flow rate ratio of the solutions (Solution 1 andSolution 2) were 40 mL/min and 20 mL/min, respectively.

A solution of complexed Celecoxib pharmaceutical formulation wasprepared by dissolving 17.5 mg/mL Celecoxib, 70 mg/mL Copovidone(copolymer of vinylpyrrolidone and vinyl acetate/Kollidon VA64) and4.375 mg/mL sodium lauryl sulfate in 2-propanol and water solventmixture having volume ratio of 2:1. The dissolution process took placeat atmospheric pressure and ambient temperature under stirring.

Both the solution mixture and solution of complexed Celecoxibpharmaceutical formulation was spray-dried (Yamato DL-410/GAS410). Theproduction parameters used were T_(inlet)=95° C., dryingairflow=0.8-0.85 m³/min, solution feed rate=6-20 mL/min, atomizationpressure=1 bar, T_(out)=60-70° C. The spray-dried formulation wasgranulated and used for iv-vivo dog PK studies.

The prepared complexed Celecoxib pharmaceutical formulation comprised 5to 40 weight % Celecoxib, 40 to 80 weight % copolymer ofvinylpyrrolidone and vinyl acetate (copovidone) and 1 to 30 weight %sodium lauryl sulfate.

Liquid dispersible granules of the complexed Celecoxib pharmaceuticalformulations were obtained by dry process. Compacts with uniformdimensions and mass were prepared of the solid Celecoxib pharmaceuticalformulations. The compacts were broken up by physical impact in order toform granulates within appropriate mesh size. After that granulates weremixed with pharmaceutically acceptable excipients.

The solid, complexed Celecoxib pharmaceutical formulation was mixed withpharmaceutically acceptable excipients. After that compacts with uniformdimensions and mass were prepared from the powder mixtures comprisingthe pharmaceutical formulation of complexed Celecoxib. The compacts werebroken up by physical impact in order to form granulates withinappropriate mesh size.

Liquid dispersible granules were prepared by compacting 400-3000 mgsolid complexed Celecoxib pharmaceutical formulation comprisingcopolymer of vinylpirrolidone and vinyl acetate and sodium laurylsulfate using a flat faced tooling with 4-23 mm diameter and pressedwith 0.1-4.5 ton load. The compacts were broken up by physical impact toform granules. The particle size of the granulates was controlled bysieving with appropriate mesh size to achieve 160-800 micrometersparticle size.

Celecoxib Pharmaceutical Compositions

The liquid dispersible granules containing the pharmaceuticalcomposition of Celecoxib were prepared by blending the granules of thecomplexed Celecoxib formulation and the unprocessed or granulatedmicronized Celecoxib. Micronized Celecoxib granules were prepared bycompacting 1 g micronized Celecoxib using a flat faced tooling with 15.8mm diameter and pressed with 1.5 ton load. The compacts were broken upby physical impact to form granules with max. 800 micrometers particlesize. The pharmaceutical compositions comprised 50-200 mg Celecoxibequivalent from the complexed Celecoxib pharmaceutical formulation and50-400 mg crystalline Celecoxib. The particle size of the unprocessed,micronized Celecoxib was between 0.5-50 micron.

Improved Apparent Solubility of Celecoxib Pharmaceutical Compositions

The apparent solubility of the complexed Celecoxib pharmaceuticalformulation, crystalline Celecoxib (micronized), granulated micronizedCelecoxib and Celecoxib pharmaceutical composition was measured byUV-VIS spectroscopy at 251 nm at room temperature. A blend comprising 10mg Celecoxib equivalent of complexed Celecoxib pharmaceuticalformulation and 20 mg granulated micronized Celecoxib was prepared. Thesamples were dispersed in ultrapurified in 1-50 mg/mL Celecoxibequivalent concentration range. The resulting solutions were filtered by100 nm disposable syringe filter. The Celecoxib content in the filtratewas measured by UV-Vis spectrophotometry and the apparent solubility wascalculated. The filtrate may contain Celecoxib particles which could notbe filtrated out using 100 nm pore size filter.

The apparent solubility of the complexed Celecoxib pharmaceuticalformulation was at least 34 mg/mL, when 50 mg/mL Celecoxib equivalentformulation was dispersed in ultrapurified water, respectively.

The apparent solubility of crystalline Celecoxib (micronized) was 2.85μg/mL when it was redispersed at 2 mg/mL concentration in ultrapurifiedwater.

The apparent solubility of granulated Celecoxib (micronized) was 0.47μg/mL when it was redispersed at 2 mg/mL concentration in ultrapurifiedwater.

The apparent solubility of Celecoxib pharmaceutical composition was atleast 5.98 mg/mL when it was redispersed at 20 mg/mL Celecoxibequivalent concentration in ultrapurified water.

Improved Dissolution Profile of Celecoxib Pharmaceutical Composition

Comparative dissolution tests were performed by dispersing the Celecoxibpharmaceutical composition, complexed Celecoxib pharmaceuticalformulation and granulated Celecoxib (micronized) in ultrapure water.(FIG. 3). The blend of the investigated pharmaceutical compositioncomprised 10 mg Celecoxib that is complexed and 20 mg granulatedmicronized Celecoxib. The investigated concentration of Celecoxib was 1mg/mL for the complexed pharmaceutical formulation and 2 mg/mL forgranulate Celecoxib (micronized) in each cases alone or combination.

Cumulative drug dissolution test was performed on the pharmaceuticalcomposition (FIG. 4). The blend of the investigated pharmaceuticalcomposition comprised 10 mg Celecoxib equivalent of the complexedCelecoxib pharmaceutical formulation and 20 mg granulated micronizedCelecoxib. The dissolution medium was FaSSIF biorelevant mediacontaining 2 mg/mL Kollidon VA64 and 0.5 mg/mL sodium lauryl sulfate. Atthe beginning 30 mg blend was dissolved in 20 mL dissolution medium andshaken for 3 minutes with 300 rpm. After shaking, it was centrifugedwith 3600 rpm for 1 minute. After centrifuging, 15 mL fluid was takenout from the top. The resulting solution was filtered by 100 nmdisposable syringe filter. The Celecoxib content in the filtrate wasmeasured by RP-HPLC measurement and the dissolved Celecoxibconcentration was calculated. The filtrate may contain Celecoxibparticles which could not be filtrated out using 100 nm pore sizefilter. The dissolution medium was replaced with 15 mL fresh FaSSIF tomaintain the sink condition. The released drug quantity was determinedevery 4 minutes be repeating the above steps.

Comparative In-Vitro PAMPA Assays

PAMPA permeability of Celecoxib pharmaceutical composition, complexedCelecoxib pharmaceutical formulation, crystalline Celecoxib (micronized)and Celebrex® was measured and compared. PAMPA permeability measurementswere performed as described by M. Kansi et al. (Journal of medicinalchemistry, 41, (1998) pp 1007) with modifications based on S. Bendels etal (Pharmaceutical research, 23 (2006) pp 2525). Permeability wasmeasured in a 96-well plate assay across an artificial membrane composedof dodecane with 20% soy lecithin supported by a PVDF membrane(Millipore, USA). The receiver compartment was phosphate buffered saline(pH 7.0) supplemented with 1% sodium dodecyl sulfate. The assay wasperformed at room temperature; incubation time was 4 hours inultrapurified water or 10-20 and 30 minutes in simulated saliva,respectively. The concentration in the receiver compartment wasdetermined by UV-VIS spectrophotometry (Thermo Scientific Genesys S10).The Celecoxib concentration in the donor compartment was 0.25-3 mg/mLfor the pharmaceutical composition and 0.25-2 mg/mL in all other cases.The blend of the pharmaceutical compositions comprised 10 mg Celecoxibequivalent of the complexed Celecoxib pharmaceutical formulation and 20mg granulated micronized Celecoxib.

The PAMPA permeability of the Celecoxib pharmaceutical compositions wasabove 0.5×10−6 cm/s when redispersed in water, FaSSIF and FeSSIF, whileit was below 0.2×10−6 cm/s for the Celebrex. PAMPA permeability of theCelecoxib pharmaceutical formulation in water, FaSSIF and FeSSIF mediawas above 1.5×10⁻⁶ cm/s. PAMPA permeability of crystalline Celecoxib(micronized) in water, FaSSIF and FeSSIF media was below 0.2×10⁻⁶ cm/s(FIG. 3).

Stability of the Celecoxib Solid Pharmaceutical Composition

PAMPA permeabilities of the Celecoxib pharmaceutical composition wereused to monitor the physical stability of the pharmaceuticalcomposition. PAMPA permeability was measured after storage at differentconditions. 3 months storage at 40° C. showed no significant decrease inthe measured PAMPA permeability under any of the conditions tested (FIG.4).

In-Vivo Pharmacokinetics In-Vivo PK Test in Large Animals

A beagle dog study using the granulated complexed pharmaceuticalformulation, micronized Celecoxib and the pharmaceutical composition wasperformed. The test items were administered orally as dispersedgranulates (complexed pharmaceutical formulation (2.5 mg/kg), micronizedCelecoxib (5 mg/kg), pharmaceutical composition (2.5 mg complexedpharmaceutical formulation+5 mg/kg micronized Celecoxib) to beagle dogsfollowing a high-fat meal. The absorption of Celecoxib from thepharmaceutical formulation was rapid with t_(250 ng/ml) at 12 minutesand t_(max) at 45 minutes. The absorption of the Celecoxib was slow forthe micronized compound reaching t_(250 ng/ml) at 45 minutes and t_(max)at 2 hours, however, at late time points plasma concentrations exceededthe plasma concentration observed for the pharmaceutical formulation.The pharmaceutical composition delivered both rapid early absorptionwith t_(250 ng/ml) at 12 minutes and higher later time point plasmaconcentrations when compared to the pharmaceutical formulation or withmicronized celecoxib (FIG. 5).

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications to adapt it to various usages and conditions.

1.-17. (canceled)
 18. A method of treating osteoarthritis, rheumatoidarthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, acutepain, and/or primary dysmenorrhea in a subject in need thereof,comprising administering to the subject in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprising: a Celecoxib complex, said complex comprising: 5-40 weight %Celecoxib, 40-80 weight % of a copolymer of vinylpirrolidone and vinylacetate, and 5-30 weight % sodium lauryl sulfate; and crystallineCelecoxib; wherein the pharmaceutical composition is prepared byblending the Celecoxib complex and the crystalline Celecoxib.
 19. Themethod of claim 18, wherein the pharmaceutical composition comprises50-200 mg Celecoxib equivalent of the Celecoxib complex.
 20. The methodof claim 18, wherein the pharmaceutical composition comprises 50-400 mgcrystalline Celecoxib.
 21. The method of claim 18, wherein thepharmaceutical composition further comprises 40-20,000 mgpharmaceutically acceptable excipients.
 22. The method of claim 18,wherein said crystalline Celecoxib is micronized Celecoxib.
 23. Themethod of claim 22, wherein the main particle size of said micronizedCelecoxib is in the range of between 3-10 μm.
 24. The method of claim18, wherein said pharmaceutical composition is suitable for oraladministration.
 25. The method of claim 24, wherein said pharmaceuticalcomposition is suitable for the preparation of liquid dispersiblegranule, sachet, orally disintegrating tablet, chewing tablet, tabletfor solution, tablet for suspension and immediate release tablet dosageforms.
 26. The method of claim 25, wherein said pharmaceuticalcomposition comprises liquid dispersible granules of the Celecoxibcomplex and crystalline Celecoxib.
 27. The method of claim 18, whereinthe Celecoxib complex is prepared by spray drying a solution mixture of2-propanol and water containing celecoxib, the copolymer ofvinylpirrolidone and vinyl acetate, and the sodium lauryl sulfate.
 28. Amethod of treating osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, ankylosing spondylitis, acute pain, and/or primarydysmenorrhea in a subject in need thereof, comprising administering tothe subject in need thereof a therapeutically effective amount of apharmaceutical composition comprising: a Celecoxib complex, said complexcomprising: 5-40 weight % Celecoxib, 40-80 weight % of a copolymer ofvinylpirrolidone and vinyl acetate, and 5-30 weight % sodium laurylsulfate; and crystalline Celecoxib.
 29. The method of claim 28, whereinthe pharmaceutical composition comprises 50-200 mg Celecoxib equivalentof the Celecoxib complex.
 30. The method of claim 28, wherein thepharmaceutical composition comprises 50-400 mg crystalline Celecoxib.31. The method of claim 28, wherein the pharmaceutical compositionfurther comprises 40-20,000 mg pharmaceutically acceptable excipients.32. The method of claim 28, wherein said crystalline Celecoxib ismicronized Celecoxib.
 33. The method of claim 32, wherein the mainparticle size of said micronized Celecoxib is in range of 3-10 μm. 34.The method of claim 28, wherein said pharmaceutical composition issuitable for oral administration.
 35. The method of claim 34, whereinsaid pharmaceutical composition is suitable for the preparation ofliquid dispersible granule, sachet, orally disintegrating tablet,chewing tablet, tablet for solution, tablet for suspension and immediaterelease tablet dosage forms.
 36. The method of claim 35, wherein saidpharmaceutical composition comprises liquid dispersible granules of theCelecoxib complex and crystalline Celecoxib.